In Silico Determination of Tinospora cordifolia Phytochemicals as Potential DPP-4 Inhibitors for Type 2 Diabetes Management

Background: Despite existing treatments, the prevalence of Type 2 diabetes mellitus (T2D) continues to rise globally, underscoring the need for novel therapeutic strategies. Medicinal plants like Tinospora cordifolia have shown potential in traditional medicine for managing various ailments, including diabetes. This study investigates the antidiabetic potential of T. cordifolia phytochemicals by targeting dipeptidyl peptidase-4 (DPP-4), a key enzyme in glucose metabolism. Methods: A library of 141 bioactive compounds from T. cordifolia was compiled and their structures retrieved from PubChem. Ligand preparation was conducted using the Schrödinger Suite, and the crystallographic structure of DPP-4 (PDB ID: 2HHA) was prepared for docking. Molecular docking, pharmacophore modeling, MM/GBSA binding energy calculations, and QSAR modeling were performed to assess binding affinities and predict inhibitory activities. Additionally, the QSAR-Toxicity Estimation Software Tool (TEST) was used to evaluate the toxicity profiles of the hit compounds. Results: Molecular docking revealed that five T. cordifolia compounds exhibited higher binding affinities than the standard drug rosiglitazone, with saponarin showing the highest affinity (-10.40 kcal/mol). MM/GBSA calculations confirmed favorable binding free energies, with saponarin exhibiting a ΔG_bind of -44.22 kcal/mol. QSAR modeling predicted that saponarin, astragalin, and tinosinenside had better pIC50 values (5.593 µM, 5.593 µM, and 5.659 µM, respectively) than rosiglitazone (5.059 µM). Pharmacophore modeling identified tinosinenside as having the highest fitness score (0.942). Toxicity assessment indicated that while tinosinenside showed potential for bioaccumulation, other compounds demonstrated moderate toxicity profiles. Conclusion: The findings suggest that saponarin, tinosinenside, and astragalin are promising candidates for DPP-4 inhibition and could be developed as novel therapeutic agents for T2D management. Further in vitro and in vivo studies are recommended to validate these computational predictions and explore the clinical potential of these phytochemicals.